The ubiquitin ligase PDZRN3 is required for vascular morphogenesis through Wnt/planar cell polarity signalling

Nat Commun. 2014 Sep 8;5:4832. doi: 10.1038/ncomms5832.

Abstract

Development and stabilization of a vascular plexus requires the coordination of multiple signalling processes. Wnt planar cell polarity (PCP) signalling is critical in vertebrates for diverse morphogenesis events, which coordinate cell orientation within a tissue-specific plane. However, its functional role in vascular morphogenesis is not well understood. Here we identify PDZRN3, an ubiquitin ligase, and report that Pdzrn3 deficiency impairs embryonic angiogenic remodelling and postnatal retinal vascular patterning, with a loss of two-dimensional polarized orientation of the intermediate retinal plexus. Using in vitro and ex vivo Pdzrn3 loss-of-function and gain-of-function experiments, we demonstrate a key role of PDZRN3 in endothelial cell directional and coordinated extension. PDZRN3 ubiquitinates Dishevelled 3 (Dvl3), to promote endocytosis of the Frizzled/Dvl3 complex, for PCP signal transduction. These results highlight the role of PDZRN3 to direct Wnt PCP signalling, and broadly implicate this pathway in the planar orientation and highly branched organization of vascular plexuses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Blood Vessels / embryology*
  • Blood Vessels / metabolism
  • Cell Polarity / genetics
  • Dishevelled Proteins
  • Endocytosis
  • Endothelial Cells / metabolism*
  • Frizzled Receptors / metabolism
  • Gene Expression Regulation, Developmental / genetics*
  • Mice
  • Mice, Knockout
  • Morphogenesis / genetics*
  • Neovascularization, Physiologic / genetics*
  • Phosphoproteins / metabolism
  • Signal Transduction
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Dishevelled Proteins
  • Dvl3 protein, mouse
  • Frizzled Receptors
  • Fzd4 protein, mouse
  • Phosphoproteins
  • Wnt Proteins
  • PDZRN3 protein, mouse
  • Ubiquitin-Protein Ligases